OVERALL: MITOCHONDRIAL PROTECTIVE INTERVENTIONS, AGING AND HEALTHSPAN P01 - SUMMARY/ABSTRACT We propose a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial targeted therapeutics are capable of resisting age-related disease and improving health and function in multiple organ systems in aging mammals. We are focused on heart, skeletal muscle and retina (vision) in aging; the vital function of each of these organs is highly reliant on mitochondrial energetics; each declines reproducibly with age and each contributes to frailty in the elderly human population. Most importantly, we show evidence that each of these age related healthspan limitations can be not just attenuated, but substantially reversed in old animals treated with a mitochondrial therapeutic agent, the tetrapeptide drug SS- 31. Thus, we have developed a strong translational goal of applying mitochondrial protective agents to achieve substantial health benefits in the aging mammalian models of mice and rats. The potential translational impact of this approach is high, as SS-31 is already in multiple phase II clinical trials, including three inspired by the prior animal studies performed by our P01 investigators. We propose three Projects: 1) Mitochondrial ROS and Cardiac Aging (Rabinovitch); 2) Mitochondrial Function and Skeletal Muscle Aging (Marcinek) and 3) Mitochondrial Function and Vision Aging (Prusky/Szeto). While each of these thee projects has their specific organ focus, each also shares a common third Aim of working jointly to establish the healthspan and lifespan benefits of SS-31 when it is continuously delivered to mice beginning at middle age, with and without the added stress of a high fat diet. We propose 5 Cores to provide vital support and services that are used by all three projects to accomplish their aims: A: Administration (Rabinovitch); B: Murine Healthspan and Lifespan, (Ladiges); C: Proteomics (MacCoss); D: Mitochondrial Protective Chemistry (Szeto) and E: Magnetic Resonance & Optics Spectroscopy (Conley).